As part of a bsic investigation of chemical messengers potentially involved in regulation of the coronary circulation we found previously that a peptide isolated from brain and human coronary arteries, neuropeptide tyrosine (NPY), caused coronary vasoconstriction. This 36-50%$ reduction in coronary blood flow (CBF) with no change in aortic blood pressure (AoP) produced myocardial ischemia, as manifested by left ventricular contractile dysfunction and myocardial tissue acidosis. Neuromodulation represents an important new concept of neural function whereby one compound modifies the action of a neurotransmitter, and it has been suggested that norepinephrine (NE) and NPY may interact in this way in sympathetic nerve endings. We tested whether there was an interaction between these compounds by infusing NPY and NE, (To increase AoP by 20 mmHg), individually and combined, directly into the coronary artery of 12-chloralose-anesthetized, open-chest dogs. We measured CBF, AoP, and as an index of mycardial ischemic injury, intramyocardial pH, by a special fiber optic probe. NE alone produced no change in pH despite a 78% increase in the product of AoP times heart rate (AoP X HR), an index of myocardial oxygen demand. Ischemia was prevented by a 135% increase in CBF, as expected. NPY alone, on the other hand decreased intramyocardial pH by 0.07 units (p Less than 0.05); this was associated with no change in AoP x HR but a 30% decrease in CBF, to confirm our previous results. NE combined with NPY produced more severe acidosis than NPY alone: intramyocrdial pH decreased by 0.13 vs 0.07 (p Less than 0.05). The increase in AoP x HR was identical to the increase with NE alone (78%), but CBF increased less than with NE alone (76 vs 135%); p Less than 0.05). We conclude that NE combined with NPY produced myocardial ischemia, in contrast to NE alone, by restricting the ability of the coronary arteries to deliver sufficient CBF to meet increased myocardial oxygen demands. Thus, an interation exists between NE and NPY and potentiates the production of myocardial ischemia by NPY.